French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS) ( French National Agency for Research on AIDS and Viral Hepatitis )

ART initiation at CD4 counts <800/mm3 could significantly reduce the probability of severe HIV-related morbidity or death in the medium term.

Tuberculosis and tuberculosis-related deaths are likely to represent a considerable proportion of morbidity and mortality among HIV-infected patients with high CD4 counts in sub-Saharan Africa. Therefore, 6-month Isoniazide Prophylaxis for Tuberculosis (IPT) and early ART could enhance each others efficacy.

Detailed Description

The main individual benefit of very early ART initiation is likely a reduction in early severe AIDS-defining and non-AIDS-defining morbidity. While the diseases that might justify earlier initiation in high-income countries are generally non-infectious (non-AIDS-defining malignancies, renal diseases and cardiovascular diseases), the leading cause of early severe AIDS-defining morbidity in sub-Saharan Africa is tuberculosis and the main causes of severe non-AIDS-defining morbidity are non-invasive bacterial diseases. As a result of poor access to diagnosis and care, some HIV-infected people die from early infectious diseases before reaching current WHO criteria for starting ART.

Although the Côte d'Ivoire National Tuberculosis Program (PNLT) does not authorize the use of prophylaxis against tuberculosis, it has allowed the Temprano trial to provide a six-month course of isoniazid (INH) prophylaxis to half of the study subjects. This will allow us to (i) put early ART in perspective with a early 6-month INH prophylaxis use, in a setting where tuberculosis is the first cause of severe HIV-associated morbidity; and (ii) to describe and assess the feasibility of a six-month course of INH prophylaxis among patients with high CD4 counts.

Some drug toxicities are immediate but reversible. If early ART is compared to no ART in the short term, these toxicities may demonstrate erroneously that early ART is unfavorable. The risks and benefits of early ART initiation should therefore be evaluated over the long term. In the Temprano trial, we will: (i) follow patients for at least 30 months and analyze the primary outcome at 30 months; (ii) follow some study subjects for 80 months and evaluate the evolution of the ART efficacy / toxicity ratio from month 30 to month 80 as a secondary endpoint, to inform future policies if early ART is found to be beneficial at 30 months.

Main objective: To assess the benefits and risks of starting ART immediately and/or to receive a 6-month IPT among HIV-infected adults with CD4 counts <800mm3 and no criteria for starting ART immediately according to the most recent WHO guidelines.

Location: Abidjan, Côte d'Ivoire.

Methods: randomized 2x2 factorial superiority trial

Main inclusion criteria: (i) HIV-1 or HIV-1+2 infection; (ii) age >18 years; (iii) nadir CD4 count <800/mm3 and no criteria for starting ART immediately according to the most recent WHO guidelines; and (iv) no active tuberculosis.

Trial arms: Arm I: ART initiation according to WHO criteria, at any time during follow-up; Arm II: INH prophylaxis (300 mg/day) for six months and ART initiation according to WHO criteria, at any time during follow-up; Arm III: immediate ART initiation, before reaching the WHO criteria; Arm IV: INH prophylaxis (300 mg/day) for six months and immediate ART initiation, before reaching the WHO criteria.

First-line ART regimens

Tenofovir / emtricitabine + efavirenz for all HIV-1-infected men and all HIV-1-infected women who meet the following requirements: on effective contraception and no history of nevirapine use for the prevention of mother-to-child transmission of HIV (PMTCT).

Tenofovir / emtricitabine + lopinavir / ritonavir for all HIV-1+2-infected patients and all women who do not use effective contraception or who have a history of nevirapine use for PMTCT.

Main secondary endpoint: Grade 3 or 4 clinical event (including renal and cardiovascular events) or laboratory test result, as defined by the ANRS classification system of drug-related adverse events.

Final primary analysis: It will be performed once the last patient has reached 30 months of follow-up. Time-dependent analyses will compare the primary outcome : (i) among patients initiating ART immediately (arms III and IV) versus patients initiating ART according to the WHO criteria (arms I and II); (ii) among patients who were prescribed a 6-months (arms II and IV) IPT versus those who were not (arms I and III).

Intermediate analysis on safety criteria:

Toxicity: all-cause mortality. We have not planned to perform any intermediate analyses for this criterion. If the number of observed deaths is higher than anticipated, however, the DSMB may decide to carry one out. In this case, we will adjust the alpha coefficient using the method suggested by Pocock to account for the large variety of available tests.

Efficacy: incidence of severe morbidity. Intermediate analysis: We have not planned any intermediate analyses for this criterion. If the number of severe morbidity evens is higher than anticipated once all patients have reached 12 months of follow-up, the DSMB may decide to carry one out. In this case, we will adjust the alpha coefficient using the method suggested by Haybittle-Peto, to account for the large variety of available tests.

* Includes publications given by the data provider as well as publications
identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ICMJE

Completed

Enrollment ICMJE

2073

Completion Date

January 2015

Primary Completion Date

January 2015 (final data collection date for primary outcome measure)

Eligibility Criteria ICMJE

Inclusion Criteria:

HIV-1 or HIV-1 + HIV-2 infection

Age >18 years

No ongoing active tuberculosis

Home address in any district of the greater Abidjan area

Written informed consent before any clinic visit or laboratory test

Clinical and immunologic status:CD4 counts <800/mm3 and no criteria for starting ART according to the most recent WHO guidelines

Exclusion Criteria:

Pregnant or breastfeeding women

HIV-2 infection alone

Clinical signs suggesting a severe disease (including tuberculosis) that has not yet been diagnosed, such as fever, wasting, diarrhea or unexplained cough (partial list)

Previous ART initiation

Known severe renal, cardiac or hepatic disease

Gender

Both

Ages

18 Years and older

Accepts Healthy Volunteers

No

Contacts ICMJE

Contact information is only displayed when the study is recruiting subjects

Listed Location Countries ICMJE

Côte D'Ivoire

Removed Location Countries

Administrative Information

NCT Number ICMJE

NCT00495651

Other Study ID Numbers ICMJE

ANRS 12136 TEMPRANO

Has Data Monitoring Committee

Yes

Responsible Party

French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS) ( French National Agency for Research on AIDS and Viral Hepatitis )

Study Sponsor ICMJE

French National Agency for Research on AIDS and Viral Hepatitis

Collaborators ICMJE

Gilead Sciences

Merck Sharp & Dohme Corp.

Investigators ICMJE

Principal Investigator:

Xavier Anglaret, MD, PhD

Université Bordeaux 2

Principal Investigator:

Serge Eholié, MD, MSc, Pr

CHU de Treichville, Abidjan

Information Provided By

French National Institute for Health and Medical Research-French National Agency for Research on AIDS and Viral Hepatitis (Inserm-ANRS)